柳叶刀发表中国原研药乳腺癌研究
西达本胺（妥西司他、妥诺司他）是中国自主研发的国际首个亚型选择性组蛋白去乙酰化酶（HDAC）口服抑制剂，2014年获得批准上市，用于治疗复发及难治性的外周T细胞淋巴瘤。表观遗传异常是肿瘤患者产生继发耐药的重要生物学基础，乳腺癌耐药机制前期研究表明，西达本胺作为选择性表观遗传调控剂，可以改善耐药，并且增加第三代甾体类芳香酶不可逆灭活剂依西美坦的敏感性，对于激素受体阳性晚期乳腺癌表现出令人鼓舞的抗肿瘤初步活性。
2019年4月26日，英国《柳叶刀》肿瘤学分册在线发表中国人民解放军总医院第五医学中心江泽飞、吉林大学第一医院李薇、复旦大学附属肿瘤医院胡夕春、黑龙江省肿瘤医院张清媛、辽宁省肿瘤医院孙涛、河南省肿瘤医院崔树德、中山大学附属肿瘤医院王树森、湖南省肿瘤医院欧阳取长、江苏省人民医院殷咏梅、河北省肿瘤医院耿翠芝、天津医科大学肿瘤医院佟仲生、吉林省肿瘤医院程颖、安徽省立医院潘跃银、济南市中心医院孙玉萍、南昌市第三医院王红、北京大学肿瘤医院欧阳涛、安徽医科大学第一附属医院顾康生、江苏省肿瘤医院冯继锋、浙江省肿瘤医院王晓稼、北京大学深圳医院王树滨、复旦大学附属中山医院刘天舒、沧州市中心医院高敬华、美国芝加哥西北大学范伯格医学院马西莫·克里斯托凡尼、深圳微芯生物科技宁志强和鲁先平等学者的研究报告，比较了依西美坦±西达本胺治疗激素受体阳性晚期乳腺癌绝经后患者的有效性和安全性。
ACE: A Phase III Trial of Chidamide in Combination With Exemestane in Patients With Hormone Receptor-Positive Advanced Breast Cancer (NCT02482753)
该全国多中心随机双盲安慰剂对照三期研究于2015年7月20日～2017年6月26日从中国22家癌症专科中心入组激素受体阳性HER2阴性乳腺癌至少一轮内分泌治疗（晚期或转移或辅助治疗）后疾病复发或进展、至少有一个可测量病变、各个器官功能正常、东部肿瘤学协作组（ECOG）体力状态评分0～1、血液学和生化指标正常的绝经后女性（年龄≥60岁或年龄<60岁如其血清卵泡刺激素和雌二醇浓度处于绝经后范围）患者365例。通过交互式网络反馈系统动态随机方案，将患者按2∶1随机分组，每周两次口服西达本胺30毫克（244例）或安慰剂（121例）。两组所有患者每天口服依西美坦25毫克。根据内脏转移与否对随机化进行分层。患者、研究者、研究当地工作者、资助者对治疗分组均盲。主要终点为研究者评定的无进展生存。对全部分析人群进行疗效分析，包括接受至少一次研究治疗的所有患者，并且对接受至少一次研究治疗和完成至少一份病例安全性报告表格的所有患者进行安全性分析。该研究已经达到对主要终点进行最终分析所需的事件数量。该试验已经结束入组患者，目前正在进行总生存随访。
结果，经过中位随访13.9个月（四分位：9.8～17.5），西达本胺组、安慰剂组的中位无进展生存分别为7.4、3.8个月（95%置信区间：5.5～9.2、3.7～5.5），进展或死亡风险显著减少25%（风险比：0.75，95%置信区间：0.58～0.98，P=0.033）。
西达本胺组、安慰剂组最常见的3～4级不良事件发生率：
中性粒减少症：51%、2%
血小板减少症：27%、2%
白细胞减少症：19%、2%
严重不良事件：21%、6%
治疗相关死亡：0、0
因此，该研究结果表明，对于既往内分泌治疗失败的激素受体阳性HER2阴性晚期乳腺癌患者，西达本胺＋依西美坦与安慰剂＋依西美坦相比，无进展生存显著延长，进展或死亡风险显著减少，3～4级血液学不良事件较多。西达本胺＋依西美坦可以作为此类患者的治疗新选择。
对此，哈佛大学医学院、麻省总医院癌症中心发表同期评论：从遗传学到表观遗传学，靶向激素受体阳性乳腺癌的组蛋白去乙酰化酶。
利益声明：马西莫·克里斯托凡尼教授为辉瑞、诺华等公司顾问，宁志强博士为深圳微芯生物科技副总经理，鲁先平博士为深圳微芯生物科技董事长兼总经理，所有其他作者均未声明任何利益冲突。
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Lancet Oncol. 2019 Apr 26. [Epub ahead of print]
Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial.
Zefei Jiang, Wei Li, Xichun Hu, Qingyuan Zhang, Tao Sun, Shude Cui, Shusen Wang, Quchang Ouyang, Yongmei Yin, Cuizhi Geng, Zhongsheng Tong, Ying Cheng, Yueyin Pan, Yuping Sun, Hong Wang, Tao Ouyang, Kangsheng Gu, Jifeng Feng, Xiaojia Wang, Shubin Wang, Tianshu Liu, Jinghua Gao, Massimo Cristofanilli, Zhiqiang Ning, Xianping Lu.
The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China; The First Hospital of Jilin University, Changchun, China; Fudan University Shanghai Cancer Centre, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Liaoning Cancer Hospital & Institute, Shenyang, China; Henan Cancer Hospital, Zhengzhou, China; Sun Yat-Sen University Cancer Centre, Guangzhou, China; Hunan Cancer Hospital, Changsha, China; Jiangsu Province Hospital, Nanjing, China; Tumour Hospital of Hebei Province, Shijiazhuang, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Jilin Cancer Hospital, Changchun, China; Anhui Provincial Hospital, Hefei, China; Jinan Central Hospital, Jinan, China; The Third Hospital of Nanchang, Nanchang, China; Beijing Cancer Hospital, Beijing, China; The First Affiliated Hospital of Anui Medical University, Hefei, China; Jiangsu Cancer Hospital, Nanjing, China; Zhejiang Cancer Hospital, Hangzhou, China; Beijing University Shenzhen Hospital, Shenzhen, China; Fudan University Zhongshan Hospital, Shanghai, China; Cangzhou Central Hospital, Cangzhou, China; Feinberg School of Medicine, Chicago, IL, USA; Chipscreen Biosciences, Shenzhen, China.
BACKGROUND: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer.
METHODS: We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing.
FINDINGS: Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13.9 months (IQR 9.8-17.5). Investigator-assessed median progression-free survival was 7.4 months (95% CI 5.5-9.2) in the tucidinostat group and 3.8 months (3.7-5.5) in the placebo group (HR 0.75 [95% CI 0.58-0.98]; p=0.033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported.
INTERPRETATION: Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients.
FUNDING: Chipscreen Biosciences
DOI: 10.1016/S1470-2045(19)30164-0
Lancet Oncol. 2019 Apr 26. [Epub ahead of print]
Genetics to epigenetics: targeting histone deacetylases in hormone receptor-positive metastatic breast cancer.
Seth A Wander, Laura M Spring, Aditya Bardia.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
DOI: 10.1016/S1470-2045(19)30279-7